Thinking beyond the bladder: antidiuretic treatment of nocturia

Authors


  • Disclosures Philip van Kerrebroeck has acted as a speaker and member of an Advisory Safety Board for Ferring Pharmaceuticals. Hashim Hashim has been a speaker for Ferring Pharmaceuticals. Neil Stanley has received honoraria for speaking and/or advisory board work from Ferring Pharmaceuticals, Pfizer and GlaxoSmithKline. Tove Holm-Larsen is an employee of Ferring Pharmaceuticals. Dudley Robinson has acted as a speaker and consultant to Ferring, Astellas, Recordati, Novo Nordisk, Uroplasty and Gynaecare. He has been an investigator with Ferring, Astellas, Allergan and Pfizer.

Philip E. V. van Kerrebroeck, MD, PhD, MMSc, Fellow EBU
Department of Urology, Maastricht University Medical Center, PO Box 5800, NL-6202 AZ Maastricht, The Netherlands
Tel.: + 31 43 3877258
Fax: + 31 43 3875259
Email: p.vankerrebroeck@mumc.nl

Abstract

Nocturia is a bothersome and highly prevalent urological condition characterised by the need to wake to void at night. Contrary to popular misconception, nocturia is equally common in men and women, and although its prevalence increases with age, a significant proportion of younger people are also affected. Nocturia leads to repeated fragmentation of sleep and consequently to a serious decline in daytime functioning and in overall quality of life and health. As such, its impact should not be underestimated by clinicians. Traditionally, nocturia has been regarded as a symptom of benign prostatic enlargement and/or overactive bladder syndrome, with treatment therefore directed towards increasing the capacity of the bladder to hold urine. Such treatments have proven largely ineffective in many patients, likely because nocturnal polyuria (NP), a condition that results in overproduction of urine at night, has been found to be present in the majority of nocturia patients. As such, the traditional belief that nocturia is attributable to some other underlying pathological factors, is now being replaced by the acknowledgment that it can be a distinct clinical entity with specific pathogenesis. Frequency-volume charts are an invaluable tool, recommended for routine use in clinical practice, to determine whether nocturia is a result of excessive urine production at night, or of small voided volumes (indicating bladder storage problems), or indeed a combination of these factors. Given the specific antidiuretic action of desmopressin, a synthetic analogue of the body’s own antidiuretic hormone, it should be considered as first-line therapy for patients with nocturia where NP is present.

Review Criteria

The information gathered is based on the scientific literature in peer-reviewed journals and also on consensus documents, especially the 4th International Consultation on Incontinence.

Message for the Clinic

Nocturia is a prevalent condition in men and women, with a major impact upon the quality of life of patients (and partners) because of chronic sleep fragmentation. Its multifactorial nature renders determination of individual aetiology complex, but voiding charts have proven invaluable in identifying major contributory factors in each patient and making rational treatment choices. Nocturnal polyuria is present in most patients and antidiuretic therapy is therefore an important tool.

Introduction

Is nocturia worth worrying about?

Isn’t it just a normal part of ageing?

And something which affects elderly men and can routinely be treated with prostate therapy?

These are just some of the common beliefs and misconceptions which surround the area of nocturia. The aim of this article is to address these issues and provide an overview of the latest data on the aetiology of nocturia in men and women, assess its real impact on patients, and review best practice approaches to the use of antidiuretic therapy in nocturia.

What is nocturia?

Nocturia is defined by the International Continence Society as ‘the complaint that the individual has to wake at night one or more times to void… each void is preceded and followed by sleep’ (1). While individuals who experience one void per night are therefore considered to have nocturia, it is generally accepted that most patients find the condition bothersome when they experience two or more voids per night (2,3).

Nocturia was traditionally believed to be a symptom of some other primary disorder, or just one of many lower urinary tract symptoms (LUTS) (1). The therapy and research area lacked clear delineation of the problem, standardisation of terminology and of definitions, and understanding of the significance of the condition for patients’ day-to-day lives. However, in recent years, nocturia has begun to be recognised as a clinical entity in its own right, deserving of more than cursory evaluation and treatment. Standardisation within the field has emerged, helping to establish greater clarity in diagnosis and allow comparison across studies. Nocturia is now recognised as a condition that affects a large proportion of the adult population, and which may have several causes (see Table 1). Broadly speaking, these may be related to hormonal imbalances, uncompensated heart disease, sleep problems, lifestyle factors or urological factors – the main focus of this article.

Table 1.   Potential factors underlying nocturia (4)
Urological evaluation revealsNocturnal polyuriaReduced nocturnal bladder capacity24-h polyuria
  1. AVP, arginine vasopressin; BOO, bladder outlet obstruction; BPE, benign prostatic enlargement; BPH, benign prostatic hyperplasia; BPO, benign prostatic obstruction; OAB, overactive bladder syndrome.

DefinitionNocturnal urine volume > 20% to 33% of total 24-h urinary volume (dependent on age)Urine production within normal limits; increased frequency, small voided volumes24-h urinary output exceeding 40 ml/kg body weight
Possible aetiologyImpaired circadian rhythm of AVP secretionOABPoorly controlled diabetes mellitus (type 1 or 2)
Congestive heart failureBOO (including BPE/BPH/BPO)Diabetes insipidus
Renal insufficiencyInfectionHypercalcaemia
Excessive evening fluid/caffeine intakeInterstitial cystitisPolydipsia
Diuretic medicationBladder hypersensitivity 
Oestrogen deficiencyCalculi 
Sleep apnoeaCancer 
Venous insufficiencyNeurogenic detrusor overactivity (e.g. multiple sclerosis) 
Oedema  
Hypoalbuminaemia  

Importantly, it is increasingly acknowledged that nocturia may be independent of other urological conditions, which are known to cause LUTS, such as overactive bladder syndrome (OAB) and benign prostatic hyperplasia or enlargement (BPE). In particular, a frequent but often overlooked cause of nocturia is nocturnal polyuria (NP). NP is the production of an abnormally large volume of urine during sleep [> 33% of the 24-h voided volume (1)], and has been found to contribute to nocturia in around 75% of patients (5–7). NP is thought to result from an abnormality of the circadian rhythm of secretion of the antidiuretic hormone, arginine vasopressin (AVP), or in rare cases other contributory factors may be active, as presented in Table 1.

Factors underlying nocturia may differ between individual patients, but may also coexist within one patient. It is therefore crucial that clinicians and other healthcare providers are well informed as to the characteristic ‘fingerprints’ of each aetiological factor, so that they can make treatment decisions which maximise the potential to achieve benefits for the patient.

A key issue to be aware of from the outset is that nocturia affects a large proportion of adults, and although most common in older people, is also frequently found in younger individuals who have more active lives and may find the condition especially bothersome (8). Although nocturia is the most prevalent LUTS (9), it is an under-reported condition, even amongst those with severe nocturia. In one survey of community-dwelling women, almost half of those whose sleep was interrupted by the need to void at least three times every night, reported that they did not consult their doctor because they believed nocturia to be a normal part of the ageing process, which they should just ‘put up with’ (10). Again, almost half of these patients stated that they did not know that nocturia could be treated. As will be discussed in more detail later in this article, repeated fragmentation of sleep on a nightly basis has real consequences for patients’ daytime functioning, quality of life (QoL) and overall health. Yet, as the study by Chen et al. (10) shows, even patients with severe nocturia are frequently not consulting their doctors and suffering in silence.

It is therefore incumbent upon the clinician to be alert to nocturia and to offer treatment where this may be beneficial. In Chen’s study, only 63% of patients reporting nocturia were offered treatment upon consultation. Non-treatment may be justified in some cases, namely if the patient is not bothered by the condition despite being aware of the potential link between nocturnal awakenings and poorer daytime functioning. However, it is critical that the patient has enough information from the clinician to make a well-informed decision regarding their possible treatment choices.

The clinical impact of disrupted sleep

The fundamental reason why we need to be concerned about nocturia is, for the most part, not the act of voiding at night per se, but the fact that it leads to repeated fragmentation of the patient’s sleep. But why does this fragmentation of sleep matter?

In 1971, Rechtschaffen (11) stated that ‘if sleep does not serve an absolutely vital function, then it is the biggest mistake the evolutionary process ever made’. The sleep state has endured despite strong selective pressures against it: sleep leaves animals vulnerable to predators and prevents ‘useful’ activities, such as finding food, reproduction and care of offspring. The hypothesis is therefore that sleep is essential. The precise function of sleep has been remarkably hard to define, however, and sleep is still often referred to as a ‘biological enigma’. Yet, most evidence indicates that sleep is vital for recuperation and restoration of physical and mental functioning. Indeed, sleep deprivation is reported to have been used as a torture technique during a number of conflicts, including by the Japanese during World War II, and by the Komityet Gosudarstvjennoj Biezopasnosti (KGB) during the Cold War (12).

We all know first-hand the effects of a ‘bad’ night’s sleep, and it has been shown empirically that even a single night of relatively poor sleep can have significant consequences for activities the next day (13). Poor sleep has been reported to be associated not only with daytime sleepiness, but also with deficits in daily functioning, such as impaired alertness and attention (14), mood disturbances (14), life dissatisfaction (15) and reduced performance at work (16). Furthermore, the risk of accidents is increased; fatigue is thought to be involved in 16–60% of road accidents, and even moderate sleep deprivation is at least as dangerous while driving as low-level alcohol intoxication (17,18). According to the National Sleep Foundation in the USA, sleep deprivation alone causes approximately 100,000 vehicle crashes annually, resulting in 1500 deaths (19).

The impact of poor sleep also reaches beyond behavioural consequences for daytime functioning. A recent study of the Whitehall II cohort found that a reduced sleep duration (< 8 h) was associated with increased mortality via effects on cardiovascular death (20). Disrupted sleep is also thought to interfere with biological rhythms. Recent data, presented at the annual meeting of the American Society for Cell Biology, showed that immunity in Drosophila melanogaster is stronger at night (21), which is consistent with the hypothesis that circadian proteins upregulate restorative functions, such as specific immune responses during sleep, when animals are not engaged in metabolically costly activities (22–24).

The sleep period in humans is divided into rapid eye movement (REM) sleep and non-REM sleep. REM sleep is when dreaming takes place, which accounts for 20–25% of the sleep period. Non-REM accounts for around 80% of the sleep period, and is divided into three stages (American Academy of Sleep Medicine, 2007); Stage 1 – transition from waking to sleeping, Stage 2 – true sleep, Stage 3 – slow wave sleep (SWS). SWS accounts for around 25% of sleep, and is the deep and restorative phase, characterised by slower breathing, decreased heart rate and low cerebral blood flow. The majority of SWS occurs in the first 3–4 h of the sleep period. A recent study showed that specific disruption of SWS for three nights results in disruption of glucose clearance and insulin secretion, indicating a role of SWS in the maintenance of normal glucose homeostasis (25). The implication of such findings is that reduced levels of SWS caused by sleep disruption may contribute to an increased risk of type 2 diabetes.

So what is the relevance of sleep research for the field of nocturia? Nocturia is the leading cause of sleep disturbance in adults in their fifties and above (26,27), and patients with ≥ 2 voids/night sleep for an average of only 2–3 h before being awoken by the need to void (28). In a survey by the National Sleep Foundation in the USA (26), over half (53%) of community-dwelling respondents over 55 years of age reported that nocturia disturbed their sleep every night or almost every night. The next most frequently reported reason for nightly disturbed sleep was physical pain, and this affected only 12% of respondents. Nocturia was therefore the major factor involved in sleep disturbance in this sample. It should be noted that many patients with nocturia have partners and/or families who may also be disturbed by the patient’s repeated visits to the toilet, and as such the impact of nocturia can stretch beyond the individual.

People with nocturia are significantly more likely to define themselves as having insomnia and poor sleep quality (p < 0.0001) (26). Nocturia predicted poor sleep independently of gender and comorbid medical conditions. These data reflect the fact that people with nocturia generally feel as though they sleep badly and that the majority of respondents experienced nocturia consistently every night or almost every night. Amongst patients with LUTS suggestive of BPE with or without nocturia, 90.6% of those without nocturia still rated their QoL as good or very good, compared with only 42.9% of those with nocturia (p < 0.001) (29). As all participants experienced LUTS and symptoms suggestive of BPE, it is likely that nocturia and the associated night-time awakenings are the major factors leading to reduced QoL in these patients.

The key role of nocturia in poor sleep, and the repercussions of poor sleep, are also highlighted by a recent study investigating nocturnal awakenings in American adults (30). In this study, 8937 participants aged 18 years or over were interviewed by telephone. Participation rates were high (over 80% at each of the three investigation centres). This study therefore not only involved a large population sample, but also included younger as well as older adults. Consistently across age groups (18–44, 45–64, ≥ 65 years), going to the toilet was the most frequently cited reason for nocturnal awakenings that was ‘often’ experienced. Respondents who reported awakening ≥ 3 nights/week were significantly more likely to report moderate sleepiness (p < 0.001), taking naps 5–7 days/week (p < 0.001) and taking sick leave in the last year (p < 0.001) than those awakening < 3 nights/week. As we have already seen in Bliwise et al.’s study of adults > 55 years, nocturia affected the majority of respondents every night, or almost every night. The sleep disruption normally associated with nocturia is therefore of the severity that has real clinical significance and implications for daytime functioning (26).

Patients with nocturia demonstrate significant impairments in work productivity, general activities, vitality and utility (31), and impairment increases with each additional void/night (p < 0.05). Nocturia therefore has a negative impact on how well people can carry out daily tasks and responsibilities, which can have further consequences for their employment and costs for society.

Nocturia is also associated with poorer health, and the majority of people with ≥ 2 voids per night rate their health as poor or moderate (32). In comparison with US mean values on the short-form health survey SF-36, taken from large epidemiological studies of the total population (including those with morbidity and those in good health), the impact of nocturia of ≥ 2 voids per night on health-related QoL is similar to that of type 2 diabetes and greater than that of hypertension (33). While self-rated health may be subject to a number of subjective and contextual influences, it has been shown that poorer self-rated health is associated with a greater risk of mortality in the elderly, and as such may be an important indicator of poor health and of the need to consider possible methods of improving self-rated health (34).

As patients who have ≥ 2 voids/night sleep on average for an initial period of only 2–3 h before they must wake to void, it is likely that their SWS is frequently interrupted because this deep form of sleep occurs in the first 3–4 h after retiring. The specific pattern of sleep fragmentation found in patients with nocturia may therefore be especially damaging because important restorative SWS is interrupted, and reductions in SWS are increasingly being recognised as detrimental not only to cognitive processes, but also to physiological processes such as glucose homeostasis, as discussed (25). The relationship between nocturia and type 2 diabetes is complex; it appears that the fragmentation of sleep caused by nocturia may be both a contributor and a result of diabetes in some cases (35).

Nocturnal voiding (≥ 3 episodes per night) and large nocturnal urine volumes are also associated with an increased risk of falls and fractures in the elderly subjects (36,37). As nocturia is often caused by NP, patients may experience the consequences of a negative fluid balance at night, in the form of thirst – causing the patient to rise to get a drink – and/or giddiness when standing (38,39), both of which may lead to a further increased risk of falling at night. The finding of increased fracture rates in those with nocturia is supported by a recent population-based survey of 788 elderly Japanese people (40). Incidents of falling not only cause direct distress and pain to the patient, but also place a considerable burden on the family or carer. Frequent nocturnal voiding can itself be a source of disturbance to partners and families, and 70% of caregivers indicate that nocturnal problems with older relatives, including micturition, are the principal reason for the decision to place them in a nursing home (18).

In an epidemiological study of over 6000 elderly people over 4.5 years, Asplund (41) reported that those who experienced ≥ 3 voids/night had an increased risk of death, even after adjusting for comorbid factors (heart disease, stroke and diabetes). Those who had died were more likely to have reported giddiness and poor balance, dry mouth (in women) and nocturnal drinking at the start of the study, thus suggesting that the increased mortality rate seen in elderly persons with nocturia may be associated with a negative fluid balance and increased rising to go to the bathroom and falling during the night. Intriguingly, Nakagawa also found a significantly increased risk of mortality amongst nocturics (≥ 2 voids/night) compared with those people who experienced < 2 voids/night [hazard ratio: 2.68 (95% confidence interval (CI): 1.12–6.43)] (42). This risk was independent of many possible contributing comorbidities or lifestyle factors including age, sex, body mass index, diabetes, hypertension, history of coronary heart disease, nephropathy, alcohol consumption and use of tranquilisers, hypnotics or diuretics. It is possible, therefore, that there are additional mechanisms by which nocturia may affect mortality – perhaps the fragmentation of sleep itself, and the health consequences of poor sleep, are an important mediator of the relationship between nocturnal voiding and mortality. Further studies investigating this hypothesis are warranted.

Nocturia in women: thinking beyond the bladder

Although nocturia is often thought of as a man’s disease, it is in fact just as common in women as in men. The EPIC study reported an overall prevalence in adults ≥ 18 years of age of 54.5% in women and 48.6% in men (≥ 1 void per night), and 24.0% in women and 20.9% in men (≥ 2 voids per night; Figure 1) (9). Prevalence increases with age, but a significant proportion of younger adults are also affected.

Figure 1.

 Prevalence of nocturia (≥ 1 and ≥ 2 voids/night) in men and women of different ages (9)

The possible pathophysiological factors involved in nocturia in women are broadly the same as in men, with the exclusion of the prostate (in men only) and oestrogen deficiency, which has an uncertain but possible marginal role in development of nocturia (in women only). The key urological factors most relevant to nocturia in women are NP and OAB. In the EPIC study, 74% of women with OAB had nocturia (43). Nocturia is commonly attributed to OAB and an inability of the bladder to store sufficient volumes of urine. However, around 62% of patients with OAB and nocturia have NP (44), increasing to 86% between the ages of 65 and 74 years (45). As discussed, NP is an overproduction of urine at night, and is primarily a result of deficient AVP release at night, which in turn reduces the ability of the kidney to concentrate the urine.

It is perhaps unsurprising, then, that traditional anticholinergic monotherapy for OAB demonstrates disappointing results with regard to nocturia. In OAB patients with NP, there is no significant reduction in nocturia episodes when receiving solifenacin monotherapy (44). Amongst patients with OAB and no NP, reduction in nocturia is greater, but still not large, with a mean reduction in nocturnal voiding frequency of 0.18 voids/night vs. placebo. It is also acknowledged that discontinuation rates in patients prescribed anticholinergic therapy are high (46), with around two-third of patients stopping medication by 30 days. While tolerability issues may contribute to these high rates of withdrawal, studies have indicated that a large proportion of patients discontinue because of lack of efficacy (47). Unrecognised and untreated NP could be a crucial factor in those who find anticholinergic medication to be inadequate and withdraw from treatment.

Nocturia in men: thinking beyond the prostate

Just as there is a tendency to presume that nocturia in women is attributable to OAB, there is also a propensity for clinicians to attribute nocturia in men to prostatic problems, which can obstruct the bladder outlet and cause LUTS. However, a study of men with nocturia (48) found that 83% had NP; 20% had NP alone, and 63% of patients had NP in combination with another factor such as small nocturnal bladder capacity, bladder outlet obstruction or sleep apnoea. Crucially, therefore, most male nocturia patients have NP, with or without comorbid prostatic problems.

As with traditional anticholinergic monotherapies for OAB, traditional BPE therapies fail to resolve nocturia. Transurethral resection of the prostate (TURP) has been widely reported to give unsatisfactory results in relation to nocturia, which is frequently reported to be the most bothersome aspect of the prostatic symptom complex (29). For example, nocturia responded to TURP therapy in only 20% of patients in a study by Yoshimura et al. (49). As might be expected, α1-blocker therapy and 5-α reductase inhibitor therapy are also unable to address NP and therefore nocturia persists for many treated via these methods – the mean reduction in nocturia vs. placebo was only 0.3 voids/night in two such studies of BPE therapy (50,51). Indeed, Yoong et al. (52) found that 85% of men with nocturia resistant to α1-blocker therapy had NP. A further 10% had 24-h polyuria, and only 5% had a normal nocturnal urine output. A key learning from such studies is that nocturia cannot be expected to improve if its causes are not treated. Nocturnal urine production is a crucial factor, which must be taken into account. As we have seen, NP is present in a large proportion of nocturia patients – a recent, large study estimated that 58–88% of screened nocturia patients had NP (53) – and therefore traditional BPE and OAB monotherapy will not produce satisfactory improvement of nocturia for most patients. It should also be noted that α1-blocker therapy can induce orthostatic hypotension, increasing the risk of imbalance and falls (54). The use of these medications should therefore be avoided if it is found to be unnecessary.

Nocturia diagnosis and therapy selection

The frequency-volume chart (FVC) is an invaluable tool in the assessment of patients’ urological symptoms, including nocturia. In this chart, the patient records voiding times and volumes throughout the day and night for at least 24 h, and ideally for at least 3 days. Fluid intake may also be recorded and can provide useful diagnostic information. Analysis of patients’ charts will reveal many important clues to the aetiology of nocturia, including total 24-h urine volume (evaluating 24-h polyuria), nocturnal urine volume (evaluating NP), voiding frequency and voided volumes (evaluating bladder storage/prostate problems). Figure 2 presents a simplified algorithm for the management of nocturia based on interpretation of the FVC.

Figure 2.

 Algorithm for management of nocturia

Twenty-four-hour polyuria can be a symptom of a number of underlying conditions, including endocrine disorders for which specialist referral is required (4). For patients with bladder storage problems (e.g. OAB and BPE), therapy aims to increase nocturnal bladder capacity, and appropriate treatment selection is covered elsewhere (55,56). However, if NP is present, either alone or in combination with OAB or BPE, treatment which reduces nocturnal urine volumes is needed. Assuming that patients have heeded advice regarding night-time fluid intake, and other causes of NP listed in Table 1 have been excluded, then antidiuretic therapy is an appropriate choice because it addresses insufficient AVP secretion, which results in NP and nocturia.

Antidiuretic therapy in nocturia

Desmopressin is a synthetic analogue of the body’s own antidiuretic hormone, AVP. It is a selective V2 receptor agonist and therefore has a greater specificity of action than AVP, avoiding unwanted vasopressor and uterotonic effects associated with V1 agonism. Desmopressin has a more powerful and longer-lasting antidiuretic action than AVP. It increases reabsorption of water in the distal and collecting tubules of the kidney via its action on the V2 receptor, and concentrates the urine, decreasing urine production and postponing the need to void. Figure 3 shows the relationship between decreasing urine flow and increased osmolality with increasing levels of plasma AVP.

Figure 3.

 The relationship of urine flow with urine osmolality at five different rates of solute excretion (57); previously adapted from (58). Copyright (2007). Reprinted with permission of John Wiley & Sons, Inc.

Given the specific antidiuretic action of desmopressin, it is the pharmacological therapy of choice for patients with nocturia where NP is present, and has a Level 1 evidence, Grade A recommendation from the International Consultation on Incontinence (59). It has a fast onset of action, with urine production decreasing within 30 min of oral administration (60), and can be administered as a tablet or oral lyophilisate (Melt) formulation requiring no concomitant fluid intake. The oral lyophilisate formulation has greater bioavailability than the tablet, allowing lower dosing to achieve equivalent antidiuresis, and a well-defined duration of action with different dosages in children suffering from bedwetting (61).

Improvement in nocturia with desmopressin

Several randomised placebo-controlled trials have demonstrated the efficacy of oral desmopressin in the treatment of adults with nocturia. A series of 3-week, randomised, double-blind placebo-controlled trials showed that oral desmopressin (0.1, 0.2 or 0.4 mg tablet) is effective in both men and women ≥ 18 years of age with nocturia. In these studies, clinical response was defined as ≥ 50% reduction in nocturnal voids from baseline. In the study of men, 34% of patients experienced clinical response with desmopressin, as compared with 3% of patients receiving placebo (p < 0.001) (62). The mean number of nocturnal voids reduced from 3.0 to 1.7 and from 3.2 to 2.7 respectively (p < 0.001). In women (63), results were similar; 46% of desmopressin-treated patients experienced clinical response, compared with 7% of patients on placebo (p < 0.0001). The mean number of nocturnal voids was reduced from 2.9 to 1.6 and from 2.9 to 2.4 respectively (p < 0.0001). In an additional study investigating both men and women (28), 33% of desmopressin-treated patients experienced clinical response, vs. 11% with placebo (p = 0.0014), with the mean number of nocturnal voids decreasing from 3.3 to 2.0 with desmopressin and from 2.8 to 2.4 with placebo (p < 0.0001). Long-term studies also show that efficacy is maintained and improved during 10–12 months of treatment; a rebound effect is seen when treatment is withdrawn, confirming the association between continued treatment and response (64).

Desmopressin was well tolerated in all studies and treatment-related adverse event (AE) rates were similar to placebo during the double-blind phases. The majority of AEs reported were mild in nature. In the study of men, AEs were reported in 17% and 25% of patients in the desmopressin and placebo groups respectively. The most frequently reported and possibly treatment-related AEs were headache, nausea, diarrhoea, dizziness and hyponatraemia (62). In the study of women, AEs were reported in 36% and 35% of patients in the desmopressin and placebo groups respectively. The most frequently reported AEs were headache, nausea and hyponatraemia. Serious AEs were reported in 2% of desmopressin patients (during the titration phase) and in 1% of patients on placebo in the double-blind phase (63). In the additional study investigating both men and women, 25% and 23% of patients reported AEs during the double-blind phase in the desmopressin and placebo groups, respectively, with 7% and 2% reporting treatment-related AEs. Headache, hyponatraemia and abdominal pain were the most frequently reported treatment-related AEs (28). Hyponatraemia is the main potentially serious AE associated with desmopressin use. Cases are rare, usually occurring soon after treatment is started, and the primary predictor is increasing age. Initiation of desmopressin is therefore currently not recommended for patients ≥ 65 years old. The mechanisms behind desmopressin-induced hyponatraemia are well understood, and serum sodium monitoring at baseline and early in treatment in older patients for whom treatment with desmopressin is indicated can greatly reduce their risk of developing the condition. Other advice regarding treatment administration, such as restriction of evening fluid intake and adherence to recommended dosing, should also be followed to minimise the risk of hyponatraemia (65).

Patient-related benefits of nocturia therapy

As we have seen, evidence for the benefit of OAB and BPE therapy for nocturia is limited. However, with antidiuretic treatment, nocturnal voiding is significantly and rapidly reduced, such that patients experience < 2 voids/night on average (62,63). This level of reduction is important, as studies have consistently found that most patients with < 2 voids/night experience no bother or only minor bother (2,66). This is likely to be related to the reduced sleep fragmentation associated with a smaller number of voids per night (67).

Patients’ initial sleep period is also significantly prolonged with desmopressin therapy (28), meaning that important SWS in the first part of the night is less likely to be interrupted. Van Kerrebroeck et al. (28) found that desmopressin-treated patients were significantly more likely to report that they felt fresh in the morning than patients receiving placebo (p = 0.02). Furthermore, the proportion of patients who reported nocturia as their most bothersome symptom decreased by > 50% with long-term desmopressin treatment (64).

As discussed, fragmented sleep is not a trivial matter and the impact on patients’ lives is significant. Nocturia is the leading cause of sleep disruption in adults, and as such is a risk factor for poorer QoL, reduced physical and mental health, and impaired performance at work. Preliminary cost-utility analyses suggest that, not only is QoL improved with treatment, but desmopressin can also be a cost-effective treatment option when improvements in patients’ work productivity, because of reduction in night-time voiding, are taken into account (68).

Desmopressin and the possibility of combination therapy

As noted, around 75% of community-dwelling men and women with nocturia (≥ 2 voids/night) have NP (5–7). As desmopressin is the only agent capable of effectively reducing night-time urinary output, it follows that ∼75% of people with nocturia may require desmopressin treatment to fully address the aetiology of their condition. This includes patients who have nocturia and a diagnosis of BPE or OAB, the majority of whom have comorbid NP. Nocturia will therefore persist despite treatment with α1-blockers and/or anticholinergics. This is consistent with the finding that many patients have treatment-resistant nocturia when prescribed traditional BPE and OAB therapies, and with Yoong et al.’s findings (52) that 73% of α1-adrenergic blocker-resistant BPE patients experienced ≥ 50% reduction in nocturnal voids with oral desmopressin. It is important, therefore, that FVCs are used wherever possible and early in the diagnostic process to gain a full insight into the causes of nocturia in each patient. Appropriate treatment selection, designed to address each underlying factor at the outset, is then possible. It is also important that clinicians take time to verify whether patients who have been prescribed with traditional BPE and OAB therapies are experiencing an improvement in their nocturia. If not, combination therapy using α1-adrenergic blockers and/or anticholinergics in conjunction with desmopressin should be considered.

Combination therapy is an emerging standard in the field of urology and is becoming recognised for its potential to improve patient outcomes. Clinical progression and International Prostate Symptom Scores in BPE patients are reported to be reduced in patients receiving concomitant 5-α reductase inhibitor and α1-blocker therapy compared with those receiving monotherapy (69,70). Combined anticholinergic and α1-blocker therapy has also been shown to be superior to monotherapy in men with BPE and OAB (71). The use of combination therapy to address multiple factors underlying LUTS is therefore accepted as a useful treatment strategy. It is now necessary also to enhance awareness that NP is an additional factor, which contributes specifically to nocturia in the majority of cases. It too requires treatment via antidiuretic therapy if nocturia is to be alleviated. Equipped with FVCs and a full treatment armamentarium capable of meeting the needs of patients with NP, OAB and/or BPE, clinicians have all the tools required to optimise diagnosis and treatment of nocturia patients.

Conclusions

Nocturia is an extremely prevalent condition, yet clinicians often underestimate its impact because they regard it as an inconvenience for their patients, but not a critical or life-threatening disorder. However, it is increasingly being acknowledged that nocturia represents a serious burden for a large proportion of the adult population. Nocturia is associated with repeated fragmentation of sleep, occurring every night in many cases. As such, its detrimental effects for the patient in terms of QoL, daytime performance and health status should not be overlooked. Patients with nocturia deserve a full consultation and implementation of an appropriate management strategy, just as would be expected for patients with a chronic sleep disorder. Clinicians are in fact well equipped to offer help to those who are bothered by nocturia, with a range of behavioural advice and/or pharmacological therapy available. Nocturia therapy is evolving in parallel with the developing recognition that nocturia is frequently not just a part of the OAB symptom complex in women, and BPE in men. NP is an additional and crucial factor, contributing to or independently causing nocturia in the majority of cases. The need to arise frequently, as a result of impairments in the circadian rhythm of urine excretion and AVP release (NP), is a disease created by nature that requires antidiuretic therapy. As such, desmopressin is capable of achieving clinically and statistically significant improvements in voiding frequency, sleep, bother, QoL and productivity in adults with nocturia. Use of appropriate diagnostic procedures, such as FVCs, is recommended to tailor treatment appropriately. Furthermore, clinicians should be aware of the full range of possible treatment strategies, which may necessitate combination therapy to address each aetiological factor, including NP if present.

Acknowledgement

Writing assistance for this manuscript was provided by Caroline Loat, PhD, ScopeMedical Ltd, and funding was provided by Ferring Pharmaceuticals.

Author contributions

All authors were involved in the development of content for the sections of the manuscript relating to their specific area of expertise, and all authors reviewed, provided critical revision and approved the full manuscript.

Ancillary